Module 11: Schizophrenia and Affective Disorders
Schizophrenia
Schizophrenia is a syndrome that affects around 1% of people, and is characterised by disordered thoughts, delusions, and hallucinations. The exact causes are unclear, however it is thought to be a combination of genetic and environmental factors. Patients are usually diagnosed with this syndrome after the onset of psychosis, which usually happens in late adolescence, early adulthood.
Symptoms of Schizophrenia
Positive: symptoms that are evident in patients, but not general public
Delusions are beliefs that are contrary to fact and that are not common in the groups, communities, or family to which the person belongs.
Delusions of persecution (being watched/followed)
Delusions of grandeur (one’s power, importance)
Delusions of control (being controlled by others)
Hallucinations are perception if stimuli that are not present
Auditory hallucinations - most prevalent (70%)
Visual hallucinations
Thought Disorder refers to having disorganised thoughts which can be irrational, which can be exhibited during conversation
Negative: symptoms that are present in the general public, but absent in patients
Reduced emotional response
Lack of speech
Lack of initiative and persistence
Anhedonia - inability to enjoy typically enjoyable activities
Social withdrawal
Cognitive: difficulties with cognitive tasks, thought to be produced by abnormalities in the brain regions that overlap with those involved in negative symptoms
Difficulty sustaining attention
Low psychomotor speeds
Difficulties in learning and memory
Difficulties in problem solving
Genetic and Environmental Factors
Genetics
Although there is no single “schizophrenia” gene, a rare mutation on DISC1 (disrupted in schizophrenia 1), has been associated with schizophrenia. DISC1 is linked to function in neural development and the dopamine system. DISC1 is also related to major depressive disorder and bipolar disorder.
Twin and Adoption Studies
Originally thought that if one monozygotic twin developed schizophrenia, and another did not, the difference must be environmental after birth
However, prenatal environment of monozygotic twins is not always identical - they can have different placentas (Monochorionic/Dichorionic).
Studies have found that the concordance rate for schizophrenia among monochorionic twins was 60%, but only 10.7% for dichorionic.
Paternal age has also been found to increase likelihood of schizophrenia development, due to mutations in the cells that produce sperm, which divide every 16 days after puberty
Epigenetic mechanisms (changes to gene expression induced by environmental factors) have also been linked to schizophrenia. Epigenetic changes initiated by events like exposure to toxins can be transferred to offspring during pregnancy. Disturbance to prenatal brain development is linked to schizophrenia. some genetic factors might increase the chance that a foetus is sensitive to an event which can disturb neural development.
Environmental
Epidemiology: study of the distribution of the distribution and causes of a condition in populations
Seasonality Effect
People born during late winter early spring are more likely to develop schizophrenia. This could be connected to seasonal viral epidemics.
Vitamin D Deficiency
As vitamin D plays a role on brain development, but also could be connected to seasonality effect. Taking a vitamin D supplement in the first year of life was associated with reduced incidence of schizophrenia among boys
Population Density
Seasonality effect is more prevalent in cities rather than rural areas. Connected to faster spread of viruses and higher chance of prenatal contraction. Furthermore, up until the age of 15, the longer the person lives in a city, the more likely they are to develop schizophrenia.
Prenatal Stress
Underweight Mother
More likely to give birth to a baby who will develop schizophrenia
Underweight Baby
Have higher incidence of schizophrenia
Prenatal Stressful Events
Witnessing a terrorist attack as a pregnant mother, increases the chance of offspring developing schizophrenia
Pregnancy and Birth Complications
Treating Positive Symptoms
Mesolimbic Pathway
Positive symptoms of schizophrenia are often connected to increased activity in the mesolimbic dopamine pathway (VTA → NAc, hippocampus, amygdala)
How do we know they are connected:
Agonist drugs, like cocaine or L-DOPA strongly reinforce behaviour and can produce the positive symptoms of schizophrenia
Antagonist drugs, like chlorpromazine decrease the positive symptoms or schizophrenia by blocking the dopamine receptors
Perhaps if reinforcement mechanisms in the mesolimbic dopamine pathway are activated at an inappropriate time, then behaviours, such as delusional thoughts and paranoia, might be reinforced.
Chlorpromazine was an early (classic) antipsychotic drug used to treat schizophrenia. Its prolonged use (or other antipsychotics) can have side effects that present similarly to symptoms of Parkinson’s, which suggests that using antipsychotics drastically decreases the absorption of dopamine. Further supporting the evidence, some people have shown Tardive Dyskinesia (opposite of Parkinson’s) suggesting the super sensitivity effect of prolonged use
Treating Negative Symptoms
Mesocortical Pathway
Negative and cognitive symptoms of schizophrenia are the result of neural differences in the PFC, which is the target of the mesocortical pathway. Negative symptoms are caused by Hypofrontality, decreased activity in the dorsolateral PFC. Hypofrontality may also be connected to the hyperactivity on the mesolimbic pathways. This is because the dlPFC normally exerts inhibitory control on the mesolimbic pathway.
Classic antipsychotics do not reduce negative and cognitive symptoms. One of the causes of negative and cognitive symptoms is decreased activation of dopamine receptors in the PFC, so drugs that block dopamine receptors would make symptoms worse.
Atypical antipsychotics increase dopaminergic activity in the PFC and decrease dopaminergic activity in the mesolimbic system (partial agonists - Aripiprazole). They have a very high affinity for a particular receptor, but activate that receptor less than the normal neurotransmitter would. So, in areas with too high concentration, PA would replace them, decreasing the “openness” of the receptors, but in places with too low concentration, they would bind, increasing the “openness” of the receptors.
The Role of Glutamate
Some studies suggest that decreased glutamate activity, resulting in hypofrontality, may contribute to the cognitive and negative symptoms.
Reduced concentration of glutamate in CSF in schizophrenics
Chronic low doses of PCP (indirect antagonist for glutamate receptors) can produce cognitive and negative symptoms in healthy people, as suppresses dlPFC, and reduces levels of dopamine utilisation in the dlPFC.
Affective Disorders
Major Depressive Disorder
MDD is a mood disorder that consists of unremitting depression or periods of depression that do not alternate with periods of mania
Low energy
Anhedonia
Feelings of guilt
Loss of appetite
Slower psychomotor speeds
Sleep disturbances
Thoughts of suicide
On the neural level:
Smaller volume of frontal lobes and hippocampus
Abnormal transmission and depletion of certain neurotransmitters, especially serotonin, norepinephrine, and dopamine
Blunted circadian rhythms; changes in SWS and REM sleep
Hormonal abnormalities, such as high cortisol and thyroid hormones disregulation
Bipolar Disorder
Bipolar disorder is a mood disorder characterised by cyclical periods of mania and depression.
An individual in the depression period is going to experience symptoms similar to MDD. However during mania, an individual might experience:
Euphoric feelings that seem extreme in the given context
Feelings of grandiosity
Non-stop speech and motor activity: might rapidly switch from topic to topic
Sleep disturbances
Experience of delusions
Get angry and defensive when someone contradicts them
Genetic Factors
Susceptibility for affective disorders is partially heritable
Close relatives of individuals with an affective disorder are 10 times more likely to develop one as well
Concordance rates for monozygotic twins is around 69%, whereas for dizygotic twins it is around 13%
Sleep and Circadian Rhythms:
RORA gene: involved in control of circadian rhythms; linked to MDD
RORB gene: also involved in circadian rhythms; linked to rapid cycling bipolar disorder in children.
Biological Treatments for Affective Disorders
Pharmacological Treatments
Depression:
Iproniazid
In the early 1950s was found to treat symptoms of depression
It inhibits the activity of monoamine oxidase (MAO), an enzyme which destroys excess monoamines in the terminal buttons.
Acts as an agonist that increases levels of norepinephrine, dopamine, and serotonin in synapse
Has very negative side effects
Tricyclic Antidepressants
Discovered in the 1950s
Work by inhibiting reuptake of norepinephrine and serotonin
Have less side effects compared to MAO inhibitors
However, also affect neurotransmitters other than norepinephrine and serotonin
SSRIs (Prozac, Citalopram)
Specifically inhibit reuptake of serotonin
Have antidepressant properties, reduce symptoms of obsessive-compulsive disorder, and social phobia
SNRIs (Duloxetine, Venlafaxine)
Inhibit reuptake of serotonin and norepinephrine
Does not affect reuptake of other neurotransmitters
Antidepressants may take several weeks to take full effect due to therapeutic lag
Might occur because autoreceptors need time to adjust to a higher level of serotonin, they need to get desensitised
when they are desensitised, the full effect of the antidepressants is going to be noticed
Ketamine
Is a glutamate NMDA agonist
May be used for treatment resistant depression
Research suggests that it is an effective, but short-term treatment of depression
Bipolar Disorder:
Lithium
Often used to treat bipolar disorder and has rapid effects
Best used for treating mania, but after treating mania, depressive symptoms also appear not to follow
70-80% of patients show a positive response to lithium within two weeks
Lithium does not mute emotions, but may have negative side effects (hard tremors, weight gain, excessive urine production, and thirst)
Toxic doses result in nausea, diarrhoea, motor incoordination, confusion, and coma
The exact reasons for why lithium works are unknown; suggested that it stabilises the population of serotonin receptors in the brain and prevents wide shifts in neural sensitivity; alternatively, that increases the production of neuroprotective proteins that help prevent cell death.
Electroconvulsive Therapy
Procedure
ECT is a brief electrical shock which can decrease symptoms of depression
Patient initially attached to a respirator and given an anaesthetic and a drug that paralyses muscles
Electrodes are placed on non-speech dominant side of the scalp and used to induce a seizure
A patient usually receives 3 treatments per week until maximal improvement is seen (6-12 treatments)
Effects
In contrast to antidepressants, ECT has rapid effects and may be very useful for treatment of resistant depression in a single treatment
Remission of symptoms is greater than 50%, but relapse is common
Prolonged or excessive ECT causes brain damage and long-term memory impairments, but recent improved methods may lower memory impairments
Exact mechanism is inconclusive
Vagus Nerve Stimulation
Electrical stimulation of the vagus nerve has been used to reduce depression symptoms
It is an indirect form of brain stimulation - painless with no seizures
Stimulating the vagus nerve activates several regions of the brain stem
Good for treatment-resistant depression
Transcranial Magnetic Stimulation
Studies suggest that TMS may be used to provide similar benefits to that of ECT without introducing cognitive and memory impairments (specifically to PFC)
However, TMS has a response rate of less than 30%, and long-term relapse rates are quite high, similarly to ECT
Deep Brain Stimulation
Electrodes in subgenual ACC in the medial prefrontal cortex showed high potency in treating treatment resistant depression that increased over time
Same for electrodes in NAc
Frontal Cortex, Monoamine Theory and Depression
Depression and Frontal Cortex
Deep Brain Stimulation practices show that the subgenual anterior cingulate cortex (ACC) plays a critical role in the development of depression.
Subgenual ACC may serve as a focal point in the network of brain regions involved in mood regulation
Depressed patients show increased activity of the subgenual ACC along with decreased activity in other regions of the frontal cortex
Antidepressants can decrease the activity in the subgenual ACC
How does that work on a neural level:
The subgenual anterior cingulate cortex (ACC) connects with emotion and thinking areas: the PFC, amygdala, hippocampus, and nucleus accumbens.
The PFC normally calms down the amygdala, which controls fear and negative emotions.
In depression, the subgenual ACC is overactive, which can disrupt this calming system.
Antidepressants reduce activity in the subgenual ACC, which may help lower amygdala activity—both directly and by restoring PFC control.
Monoamine Hypothesis
Monoamine hypothesis: depression is caused by insufficient activity of monoaminergic neurons, specifically serotonin and norepinephrine.
This theory is based on the fact that monoamine agonists reduce depressive symptoms, and antagonists - increase
Tryptophan Depletion Procedure (TDP)
Tryptophan is a precursor for serotonin
A low tryptophan diet followed by an amino acid drink that contains no tryptophan (so blood levels of tryptophan are low) reduces serotonin synthesis
This may cause MDD patients to relapse, but improvement with a normal diet
However, has little to no effect on healthy individuals, but lowers the mood of people with personal/family history of affective disorders
Criticisms:
As decreasing the amount of serotonin in healthy individuals has no effect, there has to be a significant physiological difference in the brains of those more susceptible
The effects of SSRIs and SNRIs take a while, so worth looking for something more direct
The exact mechanisms are still unknown
Serotonin Transporter Protein and Depression
Serotonin (5-HT) transporter proteins (5-HTT) can remove excess serotonin from the synapse via reuptake, whereas SSRIs block these proteins from working.
A portion of the gene called the promoter region for 5-HTT comes in two forms: short or long.
The likelihood of MDD and suicidality increased with the number of stressful events, but the increase was much higher for people with one or two copies of the short alleles for the 5-HTT promoter
By contrast, individuals with two long promoter alleles who had been treated with antidepressants had better long term outcomes
However, meta analyses suggest that there are no significant effects - unclear effects
Neurogenesis and Affective Disorders
In adults neurogenesis (production of new neurons) takes place in the dentate gyrus of the hippocampal formation.
It is suggested that neurogenesis plays a crucial role in affective disorders
Animal studies suggest that stressful experiences negatively impact neurogenesis in hippocampus
Additionally, antidepressant treatments might increase neurogenesis; therapeutic lag takes about the same time as maturation of new neurons
The only available option to measure neurogenesis in humans is measuring the blood volume of the dentate gyrus
Sleep Disturbances in Major Depression
Sleep problems are very common with depression (90% experience changes in sleep patterns: fragmented sleep, awaken often)
Reduced SWS and increased stage 1 NREM sleep
REM occurs earlier in the night and a higher proportion of REM in the first half of the night and more rapid eye movements.
Sleep deprivation may provide antidepressant effect, but not everyone responds to sleep deprivation treatment
People with mood swings are thought to benefit, and people who feel depressed in the morning, but better during the day
Sleep might produce a substance with a depressogenic effect